Chromatin-modifying proteins are generally thought to play broad, nonspecific roles in transcription and other cellular processes, but there is increasing evidence that chromatin components have specialized tissue and gene-specific functions during development. Histone variant H3.3 is known as the universal substrate for replication-independent nucleosome assembly at actively transcribed genes. Although H3.3 is shown to regulate transcription of many genes, I, along with Brian DeDecker and Kyle Webster, have discovered a specific role for H3.3 in repression of Notch signaling in Drosophila. We show that a major function of one of the H3.3-encoding genes, His3.3A, is activating Suppressor of Hairless (Su(H)) expression. His3.3A mutants exhibit depletion of Su(H) protein and subsequent de-repression of Notch signaling. This results in partial lethality and neuromuscular and glial migration defects at embryonic and larval stages. We demonstrate that His3.3A mutant phenotypes are rescued in two ways: by lowering Notch signaling back to more wild-type levels using a Notch loss-of-function allele, and also by ectopically expressing Su(H) using a constitutively active UAS-Su(H) construct. Given the large number of genes that are misregulated when H3.3 is depleted, we were surprised to discover that the phenotypes observed in His3.3A mutants are not caused by defects in multiple signaling pathways, but are in fact the result of overactive Notch signaling.